Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization.
Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization.
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DOI：
10.1016/j.cellsig.2009.12.003
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发表时间：
2010-04
影响因子：
4.8
通讯作者：
Law PY
中科院分区：
文献类型：
--
作者：
Chu J;Zheng H;Zhang Y;Loh HH;Law PY
μ-阿片受体（莫尔）的脱敏是阿片类药物耐受性形成的重要调节过程。通过对细胞内Ca ~（2+）释放的监测，我们发现[D-Ala_2，N-Me-Phe_4，Gly_5-ol]-脑啡肽（DAMGO）诱导的受体脱敏需要受体磷酸化和β-arrestins（βArrs）的募集，而吗啡诱导的受体脱敏则不需要。在目前的研究中，我们确定吗啡诱导的莫尔脱敏是蛋白激酶C（PKC）依赖性的。通过RNA干扰技术和亚型特异性抑制剂的研究，发现PKCε是吗啡激活的PKC亚型，也是吗啡脱敏的主要机制。相反，DAMGO不增加PKCε活性，并且DAMGO诱导的莫尔脱敏不受调节PKCε活性的影响。在受体信号复合物内的各种蛋白质中，Gαi2被吗啡激活的PKCε磷酸化。此外，将Gαi2上的三个推定的PKC磷酸化位点Ser 44、Ser 144和Ser 302突变为Ala可减弱吗啡诱导的脱敏，但不能减弱DAMGO诱导的脱敏。此外，吗啡预处理可使大麻素受体CB 1激动剂WIN 55212-2引起细胞内[Ca 2 +]i的释放，而这种脱敏作用可通过PKCε抑制剂预处理或过表达Gαi2使PKC磷酸化位点发生突变而逆转。因此，根据激动剂的不同，莫尔的激活可能导致异源脱敏和莫尔与其他Gα i偶联受体（如CB 1）之间可能的串扰。
Desensitization of the μ-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Monitoring the release of intracellular Ca2+ ([Ca2+]i), we reported that [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO)-induced receptor desensitization requires receptor phosphorylation and recruitment of β-arrestins (βArrs), while morphine-induced receptor desensitization does not. In current studies, we established that morphine-induced MOR desensitization is protein kinase C (PKC)-dependent. By using RNA interference techniques and subtype specific inhibitors, PKCε was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. In contrast, DAMGO did not increase PKCε activity and DAMGO-induced MOR desensitization was not affected by modulating PKCε activity. Among the various proteins within the receptor signaling complex, Gαi2 was phosphorylated by morphine-activated PKCε. Moreover, mutating three putative PKC phosphorylation sites, Ser44, Ser144 and Ser302 on Gαi2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca2+]i release, and this desensitization could be reversed by pretreating the cells with PKCε inhibitor or overexpressing Gαi2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other Gαi-coupled receptors, such as the CB1.
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影响因子：
4.1
作者：
BUSHFIELD, M;MURPHY, GJ;HOUSLAY, MD
通讯作者：
HOUSLAY, MD
影响因子：
3.3
作者：
Hua, XY;Moore, A;Butler, M
通讯作者：
Butler, M
影响因子：
2.9
作者：
Gavériaux-Ruff, C;Kieffer, BL
通讯作者：
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影响因子：
4.8
作者：
Krasel, C;Dammeier, S;Lohse, MJ
通讯作者：
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影响因子：
4.8
作者：
Kozasa, T;Gilman, AG
通讯作者：
Gilman, AG